The Discovery of OSI-906, a Small-molecule Inhibitor of the Insulin-like Growth Factor-1 and Insulin Receptors - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 90

Table 4.11 In vitro profile of OSI-906 in LISN and GEO cells.

Assay IC 50 (mM) Cell line

IGF-1R biochemical 0.035 -

IGF-1R 0.024 LISN/GEO

pERK1/2 0.028 LISN

p-70S6K 0.060 LISN

pAKT (Ser473) 0.130/0.110 LISN/GEO

1.275 a

IGF-1R þ 90% mouse plasma GEO

0.213 a

IGF-1R þ 90% human plasma GEO

a Percent bound drug by ultracentrifugation was 98.4% (mouse) and 96.7% (human), correlating
with the IC 50 shifts in the presence of the respective plasmas.

the presence of mouse plasma, leading to an IC 50 shift of approximately 79-
fold, whereas the least protein-binding effect was observed with human plasma,
approximately 4.7-fold. These differential plasma protein-binding shifts of OSI-
906 were consistent with direct measurements of the binding of OSI-906 to
plasma proteins from various species, as measured by % bound drug by
ultracentrafugation, and suggest that the activity of the compound to inhibit
IGF-1R in vivo will be greater in humans than in mice.

4.9 OSI-906: Selectivity Profile
As evidenced in Figure 4.8 and Table 4.11, OSI-906 is a potent inhibitor of
IGF-1R in both biochemical and mechanistic assays. To determine the overall
kinase selectivity profile of OSI-906, the compound was assayed in vitro for
inhibitory activity against a panel of kinases. 39 OSI-906 at a concentration of 1
mM did not show greater than 50% inhibition against 88 additional purified
protein kinases representing the tyrosine and serine/threonine kinase families
(Figure 4.9, Table 4.12). A follow-up study was conducted to determine IC 50
values against a key subset of kinases, where OSI-906 displayed IC 50 values of
410 mM (Table 4.13). The exquisite selectivity of OSI-906 might be rationa-
lized from the isosteric PQIP structure. 40 OSI-906 targets an intermediate
conformation of the protein that features an inactive orientation of the C-helix
(0P form) but an orientation of the activation loop more associated with the
phospho-protein (3P form) (Figure 4.10). OSI-906 enables this intermediate
conformation primarily via its interactions with the C-helix. Since induction of
this intermediate conformation appears quite rare in kinases and residues are
generally less conserved in the C-helix region across different kinases, specificity
ensues. Naturally, for the 480% homologous kinase domains of insulin
receptor (IR) and insulin receptor-related kinase (IRR), similar anities as for
the IGF-1R kinase domain are observed.
Recent reports suggest that signaling through the IGF-1R axis, specifically
through IGF-1R/IR hybrid receptors and/or IR, may also produce tumor
promoting effects. 44 IR-A has been implicated in malignant transformation 45-47
and shown in select instances to be driven by the IGF-2 ligand in an autocrine